Myelodysplastic syndromes (MDS) are clonal disorders of the HSC characterized by ineffective hematopoiesis leading to peripheral blood cytopenias, mainly anemia. Erythroid cell dysplasia is observed in 50% of early stage MDS, including refractory anemia (RA), refractory cytopenia with (RCMD) or without multilineage dysplasia, 5q-syndrome, refractory anemia with ring sideroblasts (RARS or RCMD-RS), and RA with excess of blasts (RAEB) with <10% medullary blasts (RAEB 1). Dyserythropoiesis associates with a defective maturation of erythroid precursors and an excessive apoptosis. The initial erythropoietic cell damage differs among MDS subtypes, for example, 5q-syndrome involves RPS14 haploinsufficiency, defective ribosomal biogenesis, and p53 activation, while RARS includes aberrant iron accumulation and mitochondrial stress.
Commitment of the BM progenitor cells is achieved through expression of lineage-specific transcription factors. GATA-1 is a zinc finger hematopoietic transcription factor expressed in erythroid cells, megakaryocytes, mast cells, and eosinophils. This transcription factor is required for the commitment of multipotent hematopoietic progenitor to the erythroid and megakaryocytic lineages. Mutant embryonic stem cells deleted of GATA-1 fail to give rise to mature RBCs in vitro. Deletion of GATA-1 gene in mice results in a lethal phenotype between embryonic day (E) 10.5 and E11.5 because of severe anemia. GATA-1 mutated embryos at E9.5 contain erythroid cells arrested at an early proerythroblast-like stage of their differentiation, thus demonstrating that GATA-1 is also required for the terminal erythroid cell maturation. Recently, it has been shown that alteration of Hsp70 cytosolic-nuclear shuttling is a major feature of MDS that favors GATA-1 cleavage and differentiation impairment, but not apoptosis, in dysplastic erythroblasts. Accordingly compounds which are able to restore nuclear localization of Hsp70 are highly desirable for resorting erythrocyte maturation in individuals suffering from MDS.